Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

ABSTRACT

This invention relates a method for topical treatment of glaucoma or ocular hypertension by administration of an effective intraocular pressure reducing amount of a prostaglandin derivative of PGA, PGB, PGE and PGF, in which the omega chain contains a ring structure. The invention further relates to compositions comprising said prostaglandin derivatives in an ophthalmologically compatible carrier.

This application is a continuation of Ser. No. 07/740,371, filed Jul.24, 1991, which is a continuation-in-part of Ser. No. 07/469,442, filedApr. 10, 1990 both are now abandoned.

The invention is concerned with new prostaglandin derivatives of PGA,PGB, PGE and PGF, in which the omega chain has been modified with thecommon feature of containing a ring structure, and their use for thetreatment of glaucoma or ocular hypertension. The invention relates alsoto ophthalmic compositions, containing an active amount of theseprostaglandin derivatives, and the manufacture of such compositions.

Glaucoma is an eye disorder characterized by increased intraocularpressure, excavation of the optic nerve head and gradual loss of thevisual field. An abnormally high intraocular pressure is commonly knownto be detrimental to the eye, and there are clear indications that, inglaucoma patients, this probably is the most important factor causingdegenerative changes in the retina. The pathophysiological mechanism ofopen angle glaucoma is, however, still unknown. Unless treatedsuccessfully glaucoma will lead to blindness sooner or later, its coursetowards that stage is typically slow with progressive loss of thevision.

The intraocular pressure, IOP (abbr. of intraocular pressure) can bedefined as according to the formula:

    IOP=P.sub.e +F×R

where P_(e) is the episcleral venous pressure, generally regarded asbeing around 9 mm Hg, F the flow of aqueous humor, and R the resistanceto outflow of aqueous humor through the trabecular meshwork and adjacenttissue into Schlemm's canal.

Besides passing through Schlemm's canal aqueous humor might also passthrough the ciliary muscle into the suprachoroidal space and finallyleave the eye through sclera. This uveoscleral route has been describedfor instance by Bill (1975). The pressure gradient in this case isinsignificant compared to the gradient over the interior wall ofSchlemm's canal and adjacent tissue in the former case. The flowlimiting step along the uveoscleral route is assumed to be the flow fromthe anterior chamber into the suprachoroidal space.

A more complete formula is given by:

    IOP=P.sub.e +(F.sub.t -F.sub.u)×R

where P_(e) and R are defined as above, Ft is the total outflow ofaqueous humor and F_(u) is the fraction passing via the uveoscleralroute.

IOP in human beings is normally in the range of 12-22 mm Hg. At highervalues, for instance over 22 mm Hg, there is a risk that the eye may beaffected. In one particular form of glaucoma, low tension glaucoma,damage may occur at intraocular pressure levels otherwise regarded asphysiologically normal. The reason for this could be that the eye isthese individuals is unusually sensitive to pressure. The oppositesituation is also known, that some individuals may exhibit an abnormallyhigh intraocular pressure without any manifest defects in the visualfield or optic nerve head. Such conditions are usually referred to asocular hypertension.

Glaucoma treatments can be given by means of drugs, laser or surgery. Indrug treatment, the purpose is to lower either the flow (F) or theresistance (R) which, according to formula (1) above, will result in areduced IOP; alternatively to increase the flow via the uveoscleralroute which according to formula (2) also gives a reduced pressure.Cholinergic agonists, for instance pilocarpine, reduce the intraocularpressure mainly by increasing the outflow through Schlemm's canal.

Prostaglandins, which recently have met an increasing interest asIOP-lowering substances may be active in that they will cause anincrease in the uveoscleral outflow (Crawford et al, 1987, and Nilssonet al, 1987). They do not appear, however to have any effect on theformation of aqueous humor or on the conventional outflow throughSchlemm's canal ((Crawford et al, 1987).

The use of prostaglandins and their derivatives is described forinstance in U.S. Pat. No. 4,599,353 (Bito), U.S. Pat. No. 4,883,819(Bito), U.S. Pat. No. 4,952,581 (Bito), WO89/03384 (Stjernschantz), EP170258 (Cooper), EP 253094 (Goh, Yasumasa), EP 308135 (Ueno, Ryuzo) andby Bito L. Z. et al (1983), Camras C. B. et al (1981, 1987a, 1987b,1988), Giuffre G. (1985), Kaufman P. L. (1986), Kersetter J. R. et al(1988), Lee P-Y et al (1988) and Villumsen J. et al (1989).

With respect to the practical usefulness of some of the previouslydescribed prostaglandins and derivatives, as suitable drugs for treatingglaucoma or ocular hypertension, a limiting factor is their property ofcausing superficial irritation and vasodilation in the conjunctiva. Itis probable, moreover, that prostaglandins have an irritant effect onthe sensory nerves of the cornea. Thus local side effects will arise inthe eye already when the amounts of prostaglandin administered are quitesmall--that is, already when the doses are lower than those that wouldbe desirable for achieving maximum pressure reduction. It has thus beenfound, for instance, that for this reason it is clinically impossible touse PGF₂α -1-isopropyl ester in the amount that would give maximumpressure reduction. Prostaglandins, being naturally occurring autacoids,are vary potent pharmacologically and effect both sensory nerves andsmooth muscle of the blood vessels. Since the effects caused byadministrations of PGF₂α and its esters to the eye, comprise in additionto pressure reduction also irritation and hyperemia (increased bloodflow), the doses currently practicable in clinical tests are necessarilyvery low. The irritation experienced when PGF₂α or its esters areapplied, consists mainly in a feeling of grittiness or of having aforeign body in one's eye, this being usually accompanied by increasedlacrimation.

We have now found that a solution to the problems discussed above is theuse of certain derivatives of prostaglandins A, B, E and F, in which theomega chain has been modified with the common feature of containing aring structure, for the treatment of glaucoma or ocular hypertension.

The prostaglandin derivatives have the general structure ##STR1##wherein A represents the alicyclic ring C₈ -C₁₂ and the bonds betweenthe ring and the side chains represent the various isomers. In PGA, PGB,PGE and PGF A has the formula ##STR2## The invention is based on the useof derivatives characterized by their omega chain and variousmodifications of the alpha chain is therefore possible still using theinventive concept. The alpha chain could typically be the naturallyoccurring alpha chain, which is esterified to the structure ##STR3## inwhich R₁ is an alkyl group, preferably with 1-10 carbon, especially 1-6atoms, for instance methyl, ethyl, propyl, isopropyl, butyl, isobutyl,neopentyl or benzyl or a derivative giving the final substanceequivalent properties as a glaucoma agent. The chain could preferably bea C₆ -C₁₀ chain which might be saturated or unsaturated having one ormore double bonds, and allenes, or a triple bond and the chain mightcontain one or more substituents such as alkyl groups, alicyclic rings,or aromatic rings with or without hetero atoms.

The omega chain is defined by the following formula: ##STR4## wherein Cis a carbon atom (the number is indicated within parenthesis)

B is a single bond, a double bond or a triple bond

D is a chain with 1-10 carbon atoms, preferably more than 2 and lessthan 8 atoms, and especially less than 5 atoms. The most efficientderivatives found so far has a chain with 3 atoms. The chain isoptionally interrupted by preferably not more than two hetero atoms O,S, or N, the substituents on each carbon atom being H, alkyl groups,preferably lower alkyl groups with 1-5 carbon atoms, a carbonyl group,or a hydroxyl group, whereby the substituent on C₁₅ preferably being acarbonyl group, or (R)--OH or (S)--OH: each chain D containingpreferably not more than three hydroxyl groups or more than threecarbonyl groups,

R₂ is a ring structure such as a phenyl group which is unsubstituted orhas one or more substituents selected from C₁ -C₅ alkyl groups, C₁ -C₄alkoxy groups, trifluoromethyl groups, C₁ -C₃ aliphatic acylaminogroups, nitro groups, halogen atoms, and an phenyl group; or an aromaticheterocyclic group having 5-6 ring atoms, like thiazol, imidazole,pyrrolidine, thiopene and oxazole; or a cycloalkane or a cycloalkenewith 3-7 carbon atoms in the ring, optionally substituted with loweralkyl groups with 1-5 carbon atoms. Some examples on derivatives whichwere evaluated are the following (for structure information see TableI):

(1) 16phenyl-17,18,19,20-tetranor-PGF₂α -isopropylester

(2) 17-phenyl-18,19,20-trinor-PGF₂α -isopropylester

(3) 15-dehydro-17-phenyl-18,19,20-PGF₂α -isopropylester

(4) 16-phenoxy-17,18,19,20-trinor-PGF₂α -isopropylester

(5) 17-phenyl-18,19,20-trinor PGE₂ -isopropylester

(6) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA₂ -isopropylester

(7) 15-(R)-17-phenyl-18,19,20-trinor-PGF₂α -isopropylester

(8) 16-[4-methoxy)-phenyl]-17,18,19,20-tetranor-PGF₂α -isopropylester

(9) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α -isopropylester

(10) 18-phenyl-19,20-dinor-PGF₂α -isopropylester

(20) 19-phenyl-20-nor-PGF₂α -isopropylester

(112) 20-phenyl-PGF₂α -isopropyl ester

(113) 20-(4-phenylbutyl)-PGF₂α -isopropyl ester

(114) 17-(2-thiophene)-18,19,20-trinor-PGF₂α -isopropyl ester

(115) 17-(3-thiophene)-18,19,20-trinor-PGF₂α -isopropyl ester

(116 and 117) 17-R,S-methyl-17-phenyl-18,19,20-trinor-PGF₂α -isopropylester

(118) 17-(4-trifluoromethyl phenyl)-18,19,20-trinor-PGF₂α -isopropylester

(119) 13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF₂α-isopropylester

(120) 17-(4-methylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester

(121) 17-(2-methylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester

(122) 17-(4-fluorophenyl)-18,19,20-trinor-PGF₂α -isopropyl ester

(123) 20-(methylenephenyl)-PGF₂α -isopropyl ester

(124) 17-naphthyl-18,19,20-trinor-PGF₂α -isopropyl ester

(125) 17-cyclohexyl-18,19,20-trinor-PGF₂α -isopropyl ester

(126) 17-(4-methoxyphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester

(127) 17-(3-methoxyphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester

(128) 15-cyclohexyl-16,17,18,19,20-pentanor-PGF₂α -isopropylester

The isopropyl esters have been synthesized in the examples given in thispatent application but it should be noticed that the substancesdisclosed comprises any alkyl ester of the prostaglandin derivatives,preferably with 1-10 carbon atoms and especially with 1-6 atoms, forinstance methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl orbenzyl esters.

The most preferred new derivatives at present are those in which theomega chain of the prostaglandin has the 18,19,20-trinor form andespecially the 17-phenyl analogues, such as the 15-(R)-, 15-dehydro and13,14-dihydro-17-phenyl-18,19,20-trinor forms. Such derivatives arerepresented by (3), (6), (7) and (9) in the formulas given in Table I.

These new derivatives are in general terms described as17-phenyl-18,19,20-trinor-PGF₂α -alkyl esters, especially lower alkylesters with 1-6 carbon atoms, for instance methyl, ethyl, propyl,isopropyl, butyl, isobutyl, neopentyl or benzyl esters.

In the formula given above the most preferred structure at present isobtained when the prostaglandin is a derivative of PGA₂, PGE₂, andPGF₂α,

B is a single bond or a double bond,

D is a carbon chain with 2-5, especially 3 atoms; C₁₅ having a carbonylor (S)--OH substituent and C₁₆ -C₁₉ having lower alkyl substituents, orpreferably H,

R₂ is a phenyl ring, optionally having substituents selected among alkyland alkyoxy groups.

The invention thus relates to the use of certain derivatives of PGA,PGB, PGE and PGF for the treatment of glaucoma or ocular hypertension.Among these derivatives defined above it has been found that some areirritating or otherwise not optimal, and in certain cases not evenuseful due to adverse effects and these are excluded in that the groupof prostaglandin derivatives defined above is limited to therapeuticallyeffective, that is intraocular pressure or hypertension lowering, andphysiologically acceptable derivatives. So is for instance (1)16-phenyl-17,18,19,20-tetranor-PGF₂α -isopropylester irritating whilethis can be eliminated by substituting the phenyl ring with a methoxygroup giving formula (8) which represents a therapeutically more usefulcompound.

The method for treating glaucoma or ocular hypertension comprisescontacting an effective intraocular pressure reducing amount of acomposition, as aforesaid, with the eye in order to reduce the eyepressure and to maintain said pressure on a reduced level. Thecomposition contains about 0.1-30 μg, especially 1-10 μg, perapplication of the active substance i.e. a therapeutically active andphysiologically acceptable derivative from the group defined above; thetreatment may advantageously be carried out in that one drop of thecomposition, corresponding to about 30 μl, is administered about 1 to 2times per day to the patients eye. This therapy is applicable both tohuman beings and to animals.

The prostaglandin derivative is mixed with an opthalmologicallycompatible vehicle known per se. The vehicle which may be employed forpreparing compositions of this invention comprises aqueous solutions ase.g. physiological salines, oil solutions or ointments. The vehiclefurthermore may contain opthalmologically compatible preservatives suchas e.g. benzalkonium chloride, surfactants like e.g. polysorbate 80,liposomes or polymers, for example methyl cellulose, polyvinyl alcohol,polyvinyl pyrrolidone and hyaluronic acid; these may be used forincreasing the viscosity. Furthermore, it is also possible to usesoluble or insoluble drug inserts when the drug is to be administered.

The invention is also related to opthamological compositions for topicaltreatment of glaucoma or ocular hypertension which comprise an effectiveintraocular pressure reducing amount of a prostaglandin derivative asdefined above and an opthalmologically compatible carrier, the effectiveamount comprises a dose of about 0.1-30μ in about 10-50 μg of thecomposition.

In the experiments carried out in this invention the active compound, inan amount, varying with the potency of the drug, from 30 μg to 300 μg/mlwas dissolved in a sterilized aqueous solution (saline 0.9%) containing0.5% polysorbate-80 as solubilizing agent.

The invention is illustrated by means of the following non-limitativeexamples, in which 7a and 9a are the at present preferred methods forsynthesis of compounds 7 and 9, respectively.

Synthesis of prostaglandin derivatives EXAMPLE 1 Preparation of16-phenyl-17,18,19,20-tetranor PGF₂α -isopropyl ester (1).

A 50 ml round bottom flask equipped with a magnetic stirring bar wascharged with 17.5 mg (0.04 mmol) 16-phenyl-17,18,19,20-tetranor PGF₂α(Cayman Chemical), 5 ml CH₂ Cl₂,30.2 mg (0.23 mmol)diisopropylethylamine. This solution was stirred at -10° C. and 13.5 mg(0.07 mmol) of isopropyltriflate (freshly prepared) was added. Thissolution was allowed to stand at -10° C. for 15 min and was then slowlywarmed to room temperature. When the esterification was completeaccording to TLC (usually after 3-4 h at room temperature) the solventwas removed in vacuo. The residue was diluted with 20 ml ethylacetate,washed with 2×10 ml 5% sodium hydrogencarbonate and 2×10 ml 3% citricacid. The organic layer was dried over unhydrous sodium sulfate. Thesolvent was removed in vacuo and the residue was purified by columnchromatography on silica gel-60 using ethyl acetate:aceton 2:1 aseluent. The title compound was obtained as a colourless oily substance(71% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2     (6H d)         3.3     (1H q)                                         2.8     (2H d)         5.0     (1H m)                                         3.8     (1H m)         5.3-5.7 (4H m)                                         4.1     (1H t)         7.1-7.3 (5H m)                                         ______________________________________                                    

EXAMPLE 2 Preparation of 17-phenyl-18,19,20-trinor PGF₂α -isopropylester (2)

A 50 ml round bottom flask equipped with a magnetic stirring bar wascharged with 20 mg (0.05 mmol) 17-phenyl-18,19,20-trinor PGF₂α (CaymanChemicals), 6 ml acetone, 39.2 mg (0.25 mmol) DBU and 42.5 mg (0.25mmol) isopropyl iodide. The solution was allowed to stand at roomtemperature for 24 h, the solvent was removed in vacuo and the residuewas diluted with 30 ml of ethyl acetate, washed twice with 10 ml 5%sodiumhydrogen carbonate and 10 ml 3% citric acid. The solvent wasremoved in vacuo, and the crude product was chromatographed on silicagel-60 using ethyl acetate:acetone 2:1 as eluent. The title compound (2)was obtained as an oily substance (65% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2     (6H d)         4.9     (1H m)                                         3.9     (1H m)         5.4-5.6 (4H m)                                         4.1     (1H t)         7.1-7.3 (5H m)                                         4.2     (1H m)                                                                ______________________________________                                    

EXAMPLE 3 Preparation of 15-dehydro-17-phenyl-18,19,20-trinor PGF₂α-isopropyl ester (3)

20.9 mg (0.092 mmol) DDQ was added to a solution of 10 mg (0.023 mmol)17-phenyl-18,19,20 trinor PGF₂α -isopropyl ester (2) in 8 ml dioxane.The reaction mixture immediately turned brown, the reaction mixture wasstirred at room temperature for 24 h. The precipitate formed wasfiltered, washed with 10 ml ethyl acetate, the filtrate was diluted with10 ml ethylacetate washed with 2×10 ml water, 2×10 ml NaOH IM and 20 mlbrine. The organic layer was dried on unhydrous sodium sulfate and thesolvent was removed in vacuo, the residue was purified by columnchromatography on silica gel using ethyl acetate:ether 1:1 as eluent.The title compound (3) was obtained as a colourless oily substance (76%yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3),- ppm:                       ______________________________________                                        δ                                                                       1.2     (6H d)         5.4     (2H m)                                         4.0     (1H m)         6.2     (1H d)                                         4.2     (1H m)         6.7     (1H q)                                         5.0     (1H m)         7.1-7.3 (5H m)                                         ______________________________________                                    

EXAMPLE 4 Preparation of 16-phenoxy-17,18,19,20-tetranor PGF₂α-isopropyl ester (4)

Following a procedure similar to that described in example 2 using 20 mg(0.051 mmol) 16-phenoxy-17,18,19,20-tetranor PGF₂α (Cayman Chemicals).The crude product was purified by column chromatography on silica gel-60using ethyl acetate:acetone 2:1 as eluent. The title compound (4) was anoily substance (53.2% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2     (6H d)         5.4     (2H m)                                         3.9     (3H m)         5.7     (2H m)                                         4.2     (1H m)         6.9     (3H m)                                         4.5     (1H m)         7.3     (2H m)                                         5.0     (1H m)                                                                ______________________________________                                    

EXAMPLE 5 Preparation of 17-phenyl-18,19,20-trinor PGE₂ -isopropyl ester(5)

Following a procedure similar to that described in example 2 using 10 mg(0.026 mmol) 17-phenyl-18,19,20-trinor PGE₂ (Cayman Chemicals). Thecrude product was purified by column chromatography on silica gel-60using ether as eluent. The title compound (5) was an oily substance(38.9% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2       (6H d)         5.3   (2H m)                                         3.9-4.1   (2H m)         5.6   (2H m)                                         4.9       (1H m)         7.2   (5H m)                                         ______________________________________                                    

EXAMPLE 6 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor PGA₂-isopropyl ester (6)

Following a procedure similar to that described in example 2 using 10 mg(0.026 mmol) 13,14-dihydro-17-phenyl PGA₂ (Cayman Chemicals). The crudeproduct was chromatographed on silica gel-60 using ether as eluent. Thetitle compound (6) was an oily substance (48% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2    (6H d)          5.4   (2H m)                                           4.3    (1H m)          7.3   (5H m)                                           5.0    (1H m)                                                                 ______________________________________                                    

EXAMPLE 7 Preparation of 15-(R)-17-phenyl-18,19,20-trinor PGF₂α-isopropyl ester (7) (Table II)

7.1. Preparation of1-(S)-2-oxa-3-oxo-6-(R)-(3-oxo-5-phenyl-1-trans-pentenyl)-7-(R)-(4-phenylbenzoyloxy)-cis-bicyclo[3,3,0]octane(13)

18 g (0.05 mol) alcohol (11), 32 g (0.15 mol) DCC, 39.1 g (0.5 mol) DMSO(newly distilled from CaH₂) and 30 ml DME were charged to a 200 ml flaskunder nitrogen. 0.49 g (0.005 mol) of orthophosphoric acid was added inone portion, and an exothermic reaction occured. The reaction mixturewas stirred mechanically at room temperature for 2 h, and the resultantprecipitate was filtered and washed with DME. The filtrate (12) can beused directly from Emmon condensation reaction.

To a suspension of 1.2 g (0.04 mol) NaH (80% washed with n-pentane toremove mineral oil) in 100 ml DME under nitrogen was added dropwise 12.3g (0.048 mol) dimethyl-2-oxo-4-phenylbutyl-phosphonate in 30 ml DME. Themixture was stirred mechanically for 1 h at room temperature, thencooled to -10° C. and a solution of the crude aldehyde (12) was added indropwise. After 15 min at 0° C. and 1 h at room temperature the reactionmixture was neutralized with glacial acetic acid, the solvent wasremoved under vacuum, and to the residue was added 100 ml ethyl acetate,washed with 50 ml water and 50 ml brine. The organic layer was driedover unhydrous sodium sulfate. The solvent was removed in vacuo and theresulting white precipitate filtered and washed with cold ether. Thetitle compound (13) was obtained as a crystalline substance mp134.5-135.5 (53% yield).

7.2. Preparation of1-(S)-2-oxa-3oxo-6-(R)-[3-(R,S)-hydroxy-5-phenyl-1-trans-pentenyl]-7-(R)-(4-phenylbenzoyloxy)cis-bicyclo[3,3,0]octane(14)

10 g (0.021 mol) enone (13) and 3.1 g (0.008 mol) cerouschlorideheptahydrate in 50 ml methanol and 20 ml CH₂ Cl₂ were charged to a 200ml round bottom flask equipped with a magnetic stirring bar and wascooled to -78° C. under nitrogen. 0.476 g (0.012 mol) of sodiumborohydride was added in small portions, after 30 min the reactionmixture was quenched by addition of saturated NH₄ Cl, and extracted with2×50 ml ethyl acetate. The extracts were dried and concentrated to leavea colourless oil (98% yield).

7.3. Preparation of1-(S)-2-oxa-3-oxo-6-(R)-[3-(R,S)-hydroxy-5-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo-[3,3,0]octane(15)

To a solution of 9.8 g (0.02 mol) lactone (14) in 100 ml absolutemethanol was added 1.7 (0.012 mol) potassium carbonate. The mixture wasstirred with a magnetic bar, at room temperature. After 3 h the mixturewas neutralized with 40 ml HCl 1M, and extracted with 2×50 ml ethylacetate. The extracts were then dried on unhydrous sodium sulfate andconcentrated. The crude product was chromatographed on silica gel usingethyl acetate:acetone as eluent. The title compound (15) was obtained asan oily substance (85% yield).

7.4. Preparation of1-(S)-2-oxa-3-hydroxy-6-(R)-[3-(R,S)-hydroxy-5-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo[3,3,0]octane(16)

To a solution of 3 g (0.011 mol) lactone (15) in 60 ml unhydrous THF,stirred magnetically and cooled to -78° C., 4.5 g (0.0315 mol) DIBAL-Hin toluene was added dropwise. After 2 h the reaction mixture wasquenched by addition of 75 ml methanol. The mixture was filtered, thefiltrate was concentrated in vacuo and the residue was chromatographedon silica gel-60 using ethyl acetate:acetone 1:1 as eluent. The titlecompound (16) was obtained as a semisolid substance (78% yield).

7.5. Preparation of 15-(R,S)-17-phenyl-18,19,20-trinor PGF₂α (17)

2.5 g (25 mmol) sodium methyl sulfinylmethide in DMSO (freshly preparedfrom sodium anhydride and DMSO) was added dropwise to a solution of 5.6g (12.6 mmol) 4-carboxybutyl triphenyl-phosphonium bromide in 12 mlDMSO. To the resultant red solution of the ylide was added dropwise asolution of the 1.2 g (4.2 mmol) hemiacetal (16) in 13 ml DMSO, and themixture was stirred for 1 h. The reaction mixture was diluted with 10 gice and 10 ml water and extracted with 2×50 ml ethyl acetate, whereafterthe aqueous layer was cooled, acidified with HCl 1M and extracted withethyl acetate, and then the organic layer was dried and concentrated.The resulting crude product was a colourless substance. The purity ofthe title compound (17) was estimated by TLC on silica gel using ethylacetate:acetone:acetic acid 1:1:0.2 v/v/v as eluent.

7.6. Preparation of 15-(R)-17-phenyl-18,19,20-trinor PGF₂α -isopropylester (7)

The crude product (17) was esterified following a procedure similar tothat described in example 2 the product was purified by columnchromatography on silica gel-60 using ethyl acetate as eluent and theresulting mixture of C₁₅ epimeric alcohol were separated.

The title compound (7) was obtained as a colourless oily substance (46%yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3),- ppm:                       ______________________________________                                        δ                                                                       1.2      (6H m)         5.4   (2H m)                                          3.9      (1H m)         5.6   (2H m)                                          4.15     (2H m)         7.2   (5H m)                                          4.95     (1H m)                                                               ______________________________________                                    

EXAMPLE 7a SCHEME 1 Preparation of 15-R-17-phenyl-18,19,20-trinor-PGF₂α-isopropyl ester, 7

Step a

7a-1: Preparation of 1-(S)-2-oxa-3-oxo-6 R-formyl-7R-(4-phenylbenzoyloxy) cis-bicyclo-[3,3,0]-octane 29

A mixture of alcohol 28 (20 g, 56, 8 mmol), DCC (35, 1 g, 170,0 mmol),DMSO (35,5 g, 454 mmol) and DME (80 ml) was stirred mechanically undernitrogene at ambient temperature for 5 min, [1] and thereafter oneportion of orthophosphoric acid 85% (3,3 g, 28,4 mmol) was added. Afterstirring for 2 h, at which time the reaction was completed (TLCmonitoring), the resultant precipitate was filtered off and washed withDME to give the unstable crude aldehyde 2. R_(f) =0.32 (silica gel,EtoAc: toluene 2: 1).

Step b

7a-2: Preparation of 1-(S)-2-oxa-3-oxo-6R-[3-oxo-5-phenyl-1-transpentenyl]-7R-(4-phenylbenzoyloxy)cis-bicyclo-[3,3,0]-octane 30

To a suspension of NaH (2,2 g, 74 mmol) (80% washed with n-pentane toremove mineral oil) in DME (150 ml) under nitrogene, was added dropwisedimethyl-2-oxo-4-phenyl-butyl-phosphonate (20.9 g, 81.6 mmol) preparedaccording to the method described by Corey et al [2], in DME (50 ml) andstirred mechanically for 1 h at room temperature. The mixture was thencooled to -10° C. and a solution of the crude aldehyde 29 was addeddropwise. After 15 min at 0° C. and 1 h at room temperature (TLCmonitoring) the reaction mixture was neturalized with glacial aceticacid, the solvent was removed and to the residue was added ethyl acetate(150 ml), washed with water (50 ml) and brine (50 ml). The organic layerwas dried over unhydrous sodium sulfate. This solvent was then removedin vacuo and the resulting white precipitate was filtered and washedwith cold ether. The title compound 3 was a crystaline substance mp134-135,5; yield=28 g (63%); R_(f) =0,55 (silica gel, EtoAc: toluene 2:1)

[α]²⁰ _(D) =-116 (C=1,26, CH₃ CN).

¹ H-NMR (CDCl₃ /TMS): δ=2,9 (8H m), 5.1 (1H t), 5.3 (1H m), 6.2 (1H d),6.7 (1H dd), 7.1-7.6 (10H m), 8.1 (4H d).

Step c

7a-3: Preparation of 1-(S)-2-oxa-3-oxo-6 R-(3R,S-3-hydroxy-5-phenyl-1-pentenyl)-7R-(4-phenylbenzoyloxy)cis-bicyclo-[3,3,0]-octane 31

To a stirred mixture of the above lactone 30 (16 g, 33,2 mmol) andcerous chloride heptahydrate (4,9 g, 13,28 mmol) in methanol:dichloromethane 2: 1 (100 ml) at ˜-10° C. was added sodium borohybride(0.63 g, 17.2 mmol) in small portions, and after 30 min (TLCmonitoring), the reaction mixture was quenched by addition of 1N HCl andextracted with ethyl acetate (2×100 ml). After drying over anhydroussodium sulfate, concentration in vacuo the corresponding epimericmixture of alcohols was obtained as a colourless oil; yield=15.6 g(96%); R_(f) =(silica gel, EtoAc: hexane 3: 1)

¹ H-NMR (CDCl₃ /TMS): δ=3.7 (1H m), 5,1 (1H m), 5,3 (1H m), 7,2 (5H m),7.4 (3H m), 7.6 (4H m), 8.1 (2H d).

Step d

7a-4: Preparation of 1-(S)-2-oxa-3-oxo-6 R-(3R,S-hydroxy-5-phenyl-1-pentenyl)-7 R-hydroxy-cis-bicyclo-[3,3,0]-octane32

To a solution of lactone 31 (13 g, 26.7 mmol) in methanol (50 ml) wasadded potassium carbonate (1.9 g, 13.3 mmol) with stirring at ambienttemperature for 3 h (TLC monitoring). The mixture was acidified to pH 4with 1N HCl, and the product extracted with ethylacetate (2×75 ml),where upon the organic phase was dried and evaporated to dryness. Thecrude product was subjected to flash column chromatography (silica gel,ethylacetate; acetone 1:1), giving the product 32 as a colourless oilwith a yield=5,8 g (72%); R_(f) =(silica gel, EtoAc: acetone 3: 1).

¹ H-NMR (CDCl₃ /TMS): δ=1.4 (2H m), 1.7 (4H m), 2.7 (4H m), 3.6 (1H m),3.9 (1H m), 4.9 (1H t), 7.2 (5H m).

Step e

7a-5: Preparation of 1-(S)-2-oxa-3-oxo-6 R-[3R,S-(2-tetrahydropyranyloxy)-5phenyl-1-pentenyl]-7R-7-(2-tetrahydropyranyloxy)cis-bicyclo-[3,3,0]-octane 33

To a stirred solution of alcohol 32 (4.3 g, 14 mmol), dihydropyran (4.7g, 56 mmol) in dichloromethane (30 ml) under nitrogene was addedpyridinium-4-toluene sulfonate (0.35 g, 1.4 mmol). The mixture was thenallowed to stand at room temperature for 12 h (TLC monitoring) whereupon the solution was quenched with methanol (10 ml) and the solventremoved in vacuo. The residue was diluted with ethylacetate (100 ml),washed with 5% cold sodium hydrogen carbonate (30 ml), and finally brine(30 ml) whereafter it was concentrated in vacuo. The crude product 16was used directly for the next step. R_(f) =(silica gel, ethyl acetate).

Step f

7a-6: Preparation of 1-(S)-2-oxa-3-hydroxy-6 R-[3R,S-(2-tetrahydropyranyloxy)-5-phenyl-1-pentenyl]-7R-(2-tetrahydropyranyloxy)-cis-bicyclo-[3,3,0]-octane 34

To a stirred solution of the above lactone 33 (3,6 g, 7.8 mmol) in drytoluene (60 ml) at -78° C. was added a solution of diisobutylabuminiumhydride (1,5M i tolulene. 1,3 g, 9,3 mmol) dropwise. After stirring for2 h (TLC monitoring) the reaction mixture was quenched by addition ofmethanol (60 ml). The temperature was raised to room temperature andstirring continued for 3.4 h. After filtration, the filtrate wasconcentrated in vacuo. The corresponding lactol 9 was obtained as acolourless oil. Yield=2.5 g (76%). R_(f) =0.47 (silica gel, EtoAc).

Step g

7a-7: Preparation of 11,15-bistetrahydropyranyloxy-15R,S-17-phenyl-18,19,20-trinor-PGF₂α 35

Sodium methylsulfinylmethide (2,7 g, 27,2 mmol) freshly prepared fromsodium hydride and DMSO was added dropwise to a solution of4-carboxybutyl triphenylphosphonium bromide (3,7 g, 13,7 mmol) in DMSO(40 ml). To the resultant red solution of ylide was added dropwise asolution of the lactol 34 (1,5 g, 3.9 mmol) in DMSO (15 ml) and themixture was stirred for 1 h (TLC monitoring). The reaction mixture wasdiluted with ice and water (50 ml), acidified with 1N HCl and extractedwith ethyl acetate, where upon the organic layer was dried over (Na₂SO₄), and concentrated in vacuco furnishing 10 as a slightly yellow oilwhich is used directly for the next step. R_(f) =0.3 (silica gel,EtoAc).

Step h

7a-8: Preparation of 11,15-bistetrahydropyranyloxy-15R,S-17-phenyl-18,19,20-trinor-PGF₂α -ipr ester 36

To a stirred solution of the crude product 35 (2.2 g, 3.9 mmol) inacetone (25 ml) at ±0° C., was added DBU (4.2 g, 27.0 mmol) dropwise,and the mixture was allowed to warm up to room temperature, followed bydropwise addition of isopropyl iodide (4.9 g, 23.5 mmol) withcontinuously stirring for 4 h (TLC monitoring). The mixture wastransferred to a separatory funnel, diluted with ether (100 ml), washedwith brine (30 ml), citric acid 3% (2×25 ml) and sodium hydrogencarbonate 5% (2×25 ml), dried (Na₂ SO₄) and evaporated. After flashcolumn chromatography (silica gel, ether) the corresponding ester 36 wasobtained as a colourless oil; yield=2.0 g (57%).

Step i

7a-9: Preparation of 15-R-17-phenyl-18,19,20-trinor-PGF₂α -isopropylester 7

To a stirred solution of the above ester 36 (1,97 g, 3,25 mmol) inethanol (25 ml) was added pyridinium-4-toluenesulfonate (0,1 g, 0,33mmol) and the mixture was warmed to 50° C. over a period of 3 h at whichtime the reaction was complete (TLC monitoring). The mixture wasconcentrated in vauco, the residue diluted with ethyl acetate (40 ml),washed with water (20 ml) and thereafter brine (20 ml). The organiclayer was dried. The epimeric mixture was separated by flashchromatography (silica gel, ethyl acetate) the pure isomers 2 and 7 wereobtained as a colourless oil. Isomer 7 yield=0.3 g. Isomer 2 yield=0.25g. Isomer 7 [α]²⁰ _(D) =+23° (C=0.6 CH₃ CN).

TLC Isomer 2: R_(f) =0,23 (silica gel, ethyl acetate).

TLC Isomer 7: R_(f) =0,28 (silica gel, ethyl acetate).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 1.6-1.9 (6H m), 2.1 (4H t), 2.6-2.9(4H m), 3.9 (1H m), 4.2 (2H m), 5.0 (1H m), 5.4 (2H m), 5.6 (2H m), 7,2(5H m).

EXAMPLE 8 Preparation of 16-[4-(methoxy)phenyl]-17,18,19,20-tetranorPGF₂α -isopropyl ester (8)

Following a procedure similar to that described in example 7 withmodified step 7-2, the aldehyde 12 described in step 7-2 was reactedwith dimethyl-2-oxo-3-[4-(methoxy)phenyl]-propylphosphonate and waspurified by column chromatography on silica gel-60 using ethylacetate:toluene 1:1 as eluent. A colourless oily substance was obtained(57% yield).

The title compound 16-[4-(methoxy)phenyl]-17,18,19,20-tetranor PGF₂α-isopropyl ester (8) was obtained as an oily substance, and purified bycolumn chromatography on silica gel-60 using ethyl acetate as eluent(46% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2      (6H d)         5.0   (1H m)                                          2.8      (2H d)         5.4   (2H m)                                          3.75     (3H S)         5.6   (2H m)                                          3.9      (1H m)         6.8   (2H d)                                          4.15     (1H m)         7.2   (2H d)                                          4.3      (1H m)                                                               ______________________________________                                    

EXAMPLE 9 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor PGF₂α-isopropyl ester (9)

Following a procedure similar to that described in example 7, with minormodification, 5 g (0.018 mol) enone (13) in 100 ml THF was reduced using2.03 g 10% pd/c under hydrogen atmosphere. After completion of thereaction (as determined by TLC on silica gel using ethylacetate:toluene1:1 as eluent) the mixture was filtered on celite. The filtrate wasconcentrated in vacuo and an oily substance was obtained (86% yield).

The final product 13,14-dihydro-17-phenyl-18,19,20-trinor PGF₂α-isopropyl ester containing a mixture of C₁₅ epimeric alcohols wereseparated by preparative liquid chromatography using 40% CH₃ CN in waterv/v as eluent.

    ______________________________________                                        Nuclear Magnetic Renonance spectrum (CDCl.sub.3)- ppm: δ                ______________________________________                                        1.2      (6H d)         5.0   (1H m)                                          3.6      (1H m)         5.4   (2H m)                                          3.9      (1H m)         7.2   (5H m)                                          4.15     (1H m)                                                               ______________________________________                                    

EXAMPLE 9a SCHEME 2 Preparation of13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α -isopropyl ester 9

Step k

9a-1: Preparation of1-(S)-2-oxa-3-oxo-6R-(3S-hydroxy-5-phenyl-1-trans-pentenyl)-7R-(4-phenylbenzoyloxy)cis-bicyclo-[3,3,0]-octane 38

To a stirred solution of lithium tri-sec-butylborohybride (0,5 g, 13,55mmol) [4] in dry ether (30 ml) at -120° C. under nitrogen was a solutionof enone 30 (5 g, 10,325 mmol) (in THF: ether 1: 1) (20 ml) cooled to-78° C. within a period of one minute after TLC monitoring (1 h) added.The reaction mixture was powered into a mixture of water, sodiumbisulphate and brine. The temperature was raised to ±0° C., more wateradded, and the mixture transferred to a separatory funnel. Ethyl acetate(50 ml) was added. The organic phase was dried (Na₂ SO₄), concentratedand subjected to flash column chromatography (silica gel, ethyl acetate)furnishing 38 as a white crystalline product; yield=3 g (60%); R_(f)=0.5 (silica gel, EtoAc).

[α]²⁵ _(D) =-101.59 (C=0.69 CH₃ CN).

¹ H-NMR (CDCl₃ /TMS): δ=4.1 (1H m), 5.5 (2H m), 5.3 (1H m), 7.1-7.6 (10Hm), 8.1 (4H d).

Step l

9a-2: Preparation of1-(S)-2-oxa-3-oxo-6R-(3S-hydroxy-5-phenyl-1-trans-pentenyl)-7R-hydroxy)cis-bicyclo-[3,3,0]-octane 39

To a solution of lactone 38 (9,8 g, 20,0 mmol) in methanol (100 ml) wasadded potassium carbonate (1,7 g, 12 mmol), and stirred at ambienttemperature for 3 h (TLC monitoring). The mixture was neutralized with1N HCl (40 ml) and the product extracted with ethyl acetate (2×50 ml).The organic phase was dried (Na₂ SO₄) and evaporated to dryness. Thecrude product was subjected to flash column chromatography (silica gel,ethyl acetate:acetone 1:1). The title compound 39 was obtained as acolourless oil; yield=4.9 g (85%). R_(f) =0.31 (silica gel, EtoAc).

[α]²⁰ _(D) =-20.48 (C=2.5 CH₃ CN).

¹ H-NMR (CDCl₃ /TMS): δ=1.9 (2H m), 2.7 (4H m), 3.9 (1H m), 4.1 (1H m),4.9 (1H m), 5.5 (2H m), 5.6 (1H m), 7.2 (5H m).

Step m

9a-3: Preparation of1-(S)-2-oxa-3-oxo-6R-[3S-(2-tetrahydropyranyloxy)-5-phenyl-1-trans-pentenyl]-7R-(2-tetrahydropyranyloxy)-cis-bicyclo-[3,3,0]-octane40

To a stirred solution of DIOL 39 (3.3 g, 11.6 mmol) and dihydropyran(4.4 g, 52 mmol) in dichloromethane (50 ml) under nitrogen was addedpyridinium-4-toluenesulfonate (0,3 g, 1.15 mmol). The mixture wasallowed to stand at room temperature for 16 h (TLC monitoring), thesolution was remodeled in vacuo. The residue was diluted with ether (100ml), transferred to a separatory funnel, and washed with brine (30 ml),where upon the organic layer was dried (Na₂ SO₄). When concentrated invacuo 40 was obtained as a colourless oil, which was used directly forthe next step.

R_(f) =0.57 (silica gel, ether).

Step n

9a-4: Preparation of1-(S)-2-oxa-3-oxo-6R-[3R-(2-tetrahydropyranyloxy)-5-phenyl-1-pentenyl]-7R-(2-tetrahydropyranyloxy)-cis-bicyclo-[3,3,0]-octane41

The above lactone 40 (5.5 g, 11,7 mmol) was dissolved in THF or ethanol(100 ml) and stirred under hydrogene atmosphere for 4 h (TLC monitoring)in the presence of Pd-c catalyst (2.1 g). Filtration through celite padfollowed by concentration gave pure 41 as a colourless oil which wasused directly for the next step; yield=5.3 g (97%); R_(f) =0.39 (silicagel, ether:ethyl acetate:acetic acid 50:1:0,2).

¹ H-NMR (CDCl₃ /TMS): δ=4.6 (1H m), 4.9 (1H m), 7.2 (5H m).

Step o

9a-5: Preparation of1-(S)-2-oxa-3-hydroxy-6R-[3R-(2-tetrahydropyranyloxy)-5-phenyl-1-pentenyl]-7R-(2-tetrahydropyranyloxy)-cis-bicyclo-[3,3,0]-octane42

To a stirred solution of the above lactone 41 (5.5 g, 11.7 mmol) in drytoluene (60 ml) at -78° C. was added a solution of diisobutyalbumiunhybride (1.5M i toluene. 2.0 g, 14.0 mmol) dropwise. After stirring for2 h (TLC monitoring) the reaction mixture was quenched by addition ofmethanol (60 ml). The temperature was raised to room temperature andstirring continued for 3.4 h. After filtration, the filtrate wasconcentrated in vacuo. The corresponding lactol 42 was obtained as acolourless oil; yield=3.8 g (76%); R_(f) =0.42 (silica gel, EtoAc).

Step p

9a-6: Preparation of11,15-bistetrahydropyranyloxy-13,14-dihydro-17-phenyl-18,19,20-trinor-PGF.sub.2α43

Sodium methylsulfinylmethide (4.1 g, 40.9 mmol) freshly prepared fromsodium hybride and DMSO was added dropwise to a solution of4-carboxybutyl triphenylphosphonium bromide (5.5 g, 20.5 mmol) in DMSO(40 ml). To the resultant red solution of ylide was added dropwise asolution of the lactol 42 (2,3 g, 5,9 mmol) in DMSO (15 ml) and themixture was stirred for 1 h (TLC monitoring). The reaction mixture wasdiluted with ice and water (50 ml), acidified with 1N HCl and extractedwith ethyl acetate, where upon the organic layer was dried over (Na₂SO₄), and concentrated in vacuo furnishing 43 as a slightly yellow oilwhich is used directly for the next step.

R_(f) =0.38 (silica gel, EtoAc).

Step q

9a-7: Preparation of11,15-bistetrahydropyranyloxy-13,14-dihydro-17-phenyl-18,19,20-trinor-PGF.sub.2αipr ester 44

To a stirred solution of the crude product 43 (3.27 g, 5.9 mmol) inacetone (25 ml) at ±0° C., was added DBU (6.25 g, 41.0 mmol) dropwise,and the mixture was allowed to warm up to room temperature, followed bydropwise addition of isopropyliodide (7.3 g, 35.2 mmol) withcontinuously stirring for 4 h (TLC monitoring). The mixture wastransferred to a separatory funnel, diluted with ether (100 ml), washedwith brine (30 ml), citric acid 3% (2×25 ml) and sodium hydrogencarbonate 5% (2×25 ml), dried (Na₂ SO₄) and evaporated. After flashcolumn chromatography (silica gel, ether) the corresponding ester 44 wasobtained as a colourless oil; yield=2.0 g (57%); R_(f) =0.58 (silicagel, ether).

IR (neat)=V=3521, 2939, 2870, 2327, 1730, 1685, 1454, 1352, 1246, 1201,1111, 1024.

¹ H-NMR (CDCl₃ /TMS): δ=4.6 (1H m), 5.0 (1H m), 5.4 (2H m), 7.2 (5H m).

Step r

9a-8: Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α-isopropyl ester 9

To a stirred solution of the above ester 44 (1.97 g, 3.25 mmol) inethanol (25 ml) was added pyridinium-4-toluenesulfonate (0.1 g, 0.33mmol) and the mixture was warmed to 50° C. over a period of 3 h at whichtime the reaction was complete (TLC monitoring). The mixture wasconcentrated in vacuo, the residue diluted with ethyl acetate (40 ml),washed with water (20 ml) and thereafter brine (20 ml). The organiclayer was dried and after flash column chromatography (silica gel, ethylacetate) the pure product 9 was obtained as a colourless oil; yield=1.1g (78%). R_(f) =0.24 (silica gel, EtoAc).

[α]²⁰ _(D) =+42.32 (C=0.6 CH₃ CN).

IR (neat)=V=3387, 3060, 3024, 2978, 2932, 2863, 2361, 2346, 1728, 1653,1603, 1560, 1507, 1497, 1453, 1438, 1374, 1311, 1248, 1181, 1146, 1109,1029, 967, 820, 747, 723, 700, 665.

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 1.6-1.9 (10H m), 2.3 (4H t), 2.6-2.9(4H m), 3.65 (1H m), 3.9 (1H m), 4.2 (1H m), 5.0 (1H m), 5.4 (2H m), 7.2(5H m).

Step s

9a-9: Preparation of13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF₂α -i pr ester 119

To a stirred solution of phenylbaric acid (0.15 g, 1.23 mmol) indichloromethane in the presence of activated molecular sieves 4 Å wasadded ester 9 (0.265 g, 0.61 mmol). The mixture was allowed to stand atroom temperature for 20 min to form 9,11-boronate to protect9,11-hydroxyl groups. To the boronate in dichloromethane was addedpyridinium chlorochromate on alumina (328 mg, 1.52 mmol) to give thecorresponding 15-dehydro analogue. After completion of the reactionether (50 ml) was added, filtered, washed with ether, the ether layerwas washed with sodium bicarbonate 5% (2×20 ml), dried on (Na₂ SO₄) andevaporated in vacuo. The crude product was subjected to flash columnchromatography (silica gel, ethyl acetate:hexane 1:0,1) furnishing 119as a colourless oil; yield=43%.

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 2.8 (2 h m), 2.9 (2H m),3.9 (1H m), 4.2 (1H m), 5.0 (1H m), 5.4 (2H m), 7.2 (5H m).

EXAMPLE 10 Preparation of 18-phenyl-19,20-trinor PGF₂α -isopropyl ester(10).

Following a procedure similar to that described in example (7) withmodified step 7-2. The aldehyde (12) described in 7-2 was reacted withdimethyl-2-oxo-5-phenyl pentyl phosphonate gave a crystalline substancetrans-enone lactone (67% yield).

The final product 18-phenyl-19,20-dinor PGF₂α -isopropyl ester (10) waspurified by column chromatography on silica gel-60 using ethyl acetateas eluent gave a colourless oil (41% yield).

    ______________________________________                                        1.2      (6H d)         5.0   (1H m)                                          3.95     (1H m)         5.4   (2H m)                                          4.10     (1H m)         5.6   (2H q)                                          4.20     (1H m)         7.2   (5H m)                                          ______________________________________                                    

EXAMPLE 11 Preparation of 19-phenyl-20-nor-PGF₂α -isopropyl ester (20)

Following a procedure similar to that described in example (7) withmodified step (7-2).

The aldehyde (12) described in (7-2) was reacted withdimethyl-2-oxo-6-phenyl-hexylphosphonate gave a colourless oiltrans-enone lactone (56% yield).

The final product 19-phenyl-20-nor-PGF₂α -isopropyl ester (20) was acolourless oil, and was purified by column chromatography on silicagel-60 using ethyl acetate as eluent (30% yield).

    ______________________________________                                        Nuclear Magnetic Resonance spectrum (CDCl.sub.3)-ppm: δ                 ______________________________________                                        1.2    (6H d)          5.0   (1H m)                                           2.6    (2H t)          5.4   (2H m)                                           3.9    (1H m)          5.5   (2H t)                                           4.1    (1H m)          7.2   (5H m)                                           4.2    (1H m)                                                                 ______________________________________                                    

EXAMPLE 12 Preparation of13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor PGF₂α isopropyl ester

13,14-dihydro-17-phenyl-18,19,20-trinor PGF₂α isopropyl ester containsthree hydroxyl groups (on C9, C11 and C15). Therefore selectiveoxidation with pyridinium chlorochromate was impossible, and the use ofa proper protective group is necessary. The C₁₅ -dehydro PG analogue wassynthesised from the appropriate C₁ -alkyl ester by initial protectionof the C9 and C11 hydroxyl groups with 2 mol. excess phenylboronic acid(Tethr. Lett. 31(1975) 2647-2650). The formation of the cyclic boronateproceeds rapidly at room temperature in the presence of activatedmolecular sieve to give the cyclic 9,11-boronate ester. Oxidation withpyridinium chlorochromate adsorbed on alumina proceeds very smoothly togive the protected C₁₅ -keto ester, which was deprotected and isolatedby column chromatography on silica gel.

13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α isopropyl ester (265 mg,0.61 mmol) in dichloromethane (1 ml) was added to a solution ofphenylboronic acid (149 mg, 1.22 mmol) in dichloromethane (3 ml) in thepresence of activated molecular sieve 4 Å. The solution was allowed tostand at room temperature for 30 min to form the 9,11-boronatecarboxylate ester. The boronate ester was directly treated withpyridinium chlorochromate (262 mg, 1.22 mmol) adsorbed on alumina (1.3g). The mixture was then allowed to stand at room temperature for 4 h(TLC monitoring). The mixture was diluted with ether (20 ml), whereafterthe solid was filtered and washed with 3×10 ml portions of ether. Thecombined filtrate was evaporated. The residue was then diluted withethyl acetate (30 ml) and washed with sodium hydroxide 0.5N (3×10 ml)and water (20 ml). The organic layer was dried over (Na₂ SO₄), andconcentrated in vacuo. The residue was dissolved in THF (10 ml) followedby addition of H₂ O₂ (0.5 ml) to remove the protecting group. Ethylacetate (30 ml) was added and the mixture was washed with brine (10 ml).The organic layer was dried over sodium sulfate, concentrated andsubjected to flash column chromatography (silicagel, ether) which gavethe desired product as a colourless oil. Yield=53%.

R_(f) =0.46 (silicagel, EtOAc).

H-NMR (CDCl₃ /TMS): δ=1.2 (d,6H), 2.3 (t,4H), 2.5 (t,2H), 2.7 (t,2H),2.9 (t,2H), 3.8 (m,1H), 4.2 (m,1H), 5.0 (m,1H), 5.4 (m,2H), 7.2 (m,5H).

EXAMPLE 13 Preparation of 20-phenyl-PGF₂α -isopropyl ester. 112

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-7-phenyl heptyl phosphonate giving a colourless oiltrans-enone lactone (40,8% yield).

The final product 20-phenyl-PGF₂α -isopropyl ester 112 was a colourlessoil, and was purified by column chromato-graphy on silica gel-60 usingethyl acetate as eluent (34,0% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.9 (1H m), 4.0 (1H m),4.1 (1H m), 5.0 (1H m), 5.4 (2H m), 5.5 (2H m), 7.2 (5H m).

EXAMPLE 14 Preparation of 20-(4-phenyl butyl) PGF₂α -isopropyl ester.113

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in step 7-1 wasreacted with dimethyl-2-oxo-11-phenyl undecane phosphonate and waspurified by column chromatography on silica gel-60 using ethyl acetate;toluene 1: 2 as eluent. A colourless oily substance was obtained (27.7%yield).

The title compound 24-phenyl-21,22,23,24-tetrahomo PGF₂α -isopropylester 113 was obtained as an oily substance, and purified by columnchromatography on silica gel-60 using ethyl acetate as eluent (45,8%yield). ¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 1.4 (4H m), 2.7 (2H t), 3.9(1H m), 4.1 (1H m), 4.2 (1H m), 5.0 (1H m), 5.4 (2H m), 5.5 (2H m), 7.2(5H m).

EXAMPLE 15 Preparation of 17-(2-thiophene)-18,19,20-trinor-PGF₂α-isopropyl ester 114

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(2-thiophene)-butyl phosphonate giving acolourless oil trans-enone lactone (78,5% yield).

The final product 17-(2-thiophene)-18,19,20-trinor-PGF₂α -isopropylester 114 was a colourless oil, and was purified by columnchromatography on silica gel-60 using dichloro-methane:isopropanol 1:0,1as eluent, the chromatography was repeated using ethyl acetate:hexane1:0,5 as eluent affords a colourless oil.

¹ H-NMR (CDCl₃ /TMS): δ=1,2 (6H d), 2.6 (2H t), 3.9 (1H m), 4.1 (1H m),4.2 (1H m), 5.0 (1H m), 5.4 (2H m), 5.5 (2H t), 7.2 (5H m).

EXAMPLE 16 Preparation of 17-(3-thiophene)-18,19,20-trinor-PGF₂α-isopropyl ester 115

Following a procedure similar to that described in example 7a withmodified step 7a-2, the aldehyde 29 described in 7a-1 was reacted withdimethyl-2-oxo-4-(3-thiophene)-butyl-phosphonate giving a colourless oiltrans-enone lactone (51% yield).

The final product 17-(3-thiophene)-18,19,20-trinor-PGF₂α -isopropylester 115 was a colourless oil, and was purified by columnchromatography on silica gel-60 using dichloro-methane:isopropanol 1:0,1as eluent. The chromatography was repeated using ethyl acetate:hexane1:0,05 as eluent which affords a colourless oil. The product was driedunder vacuum over night.

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.9 (1H m), 4.1 (1H m),4.1 (1H m), 4.9 (1H m), 5.4 (2H m), 6.8 (2H d), 7.2 (1H m).

EXAMPLE 17 AND 18 Preparation of17-R-methyl-17-phenyl-18,19,20-trinor-PGF₂α -isopropyl ester 116

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2. The aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-R,S-methyl-4-phenyl-butyl-phosphonate giving acolourless oil trans-enone lactone (61% yield).

The product 7-R,S-methyl-17-phenyl-18,19,20-trinor-PGF₂α -isopropylester was a colourless oil, and was purified by column chromatography onsilica gel-60 using ethyl acetate as eluent. This product containing C17epimeric mixture was separated by preparative liquid chromatographyusing 38% CH₃ CN in water V/V as eluent furnishing 116 and 117 as acolourless oil.

¹ H-NMR (CDCl₃ /TMS): σ=1.2 (6H d), 3.7 (2H m), 4.1 (1H m), 4.9 (1H m),5.4 (2H m), 5.5 (2H t), 7.2 (5H m).

EXAMPLE 19 Preparation of 17-(4-trifluoromethylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester 118

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2. The aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(4-trifluoromethyl)-phenyl-butyl-phosphonategiving a colourless oil trans-enone lactone (60% yield).

The final product 17-(4-trifluoromethyl)-phenyl-18,19,20-trinor-PGF₂α-isopropyl ester 118 was a colourless oil, and was purified by columnchromatography on silica gel-60 using ethyl acetate:hexane 1:0.2 aseluent (30% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.9 (1H m), 4.1 (2H m),5.0 (1H m), 5.4 (2H m), 5.5 (2H m), 7.3 (2H m), 7.6 (2H d).

EXAMPLE 20 Preparation of 17-(4-methylphenyl)-18,19,20-trinor-PGF₂α-isopropyl ester 120

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2. The aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(4-methyl)-phenyl butyl phosphonate giving acolourless oil trans-enone lactone (61% yield).

The final product 17-(4-methyl)-phenyl-18,19,20-trinor-PGF₂α -isopropylester 120 was a colourless oil, and was purified by columnchromatography on silica gel-60 using ethyl acetate as eluent.

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.9 (1H m), 4.1 (2H m),5.0 (1H m), 5.4 (2H m), 5.5 (2H t), 7.1 (5H s).

EXAMPLE 21 Preparation of 17-(2-methylphenyl)-18,19,20-trinor-PGF₂α-isopropyl ester 121

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(2-methyl)-phenyl butyl phosphonate giving acolourless oil trans-enone lactone (55% yield).

The final product 17-(2-methyl)-phenyl-18,19,20-trinor-PGF₂α -isopropylester 121 was a colourless oil, and was purified by columnchromatography on silica gel-60 using ethyl acetate as eluent (20%yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H m), 3.9 (1H m), 4.1 (2H m),5.0 (1H m), 5.4 (2H m), 5.6 (2H t), 7.1 (4H m).

EXAMPLE 22 Preparation of 17-(4-fluorophenyl)-18,19,20-trinor-PGF₂α-isopropyl ester 122

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(4-fluoro)-phenyl butyl phosphonate and waspurified by column chromatography on silica gel-60 using ethylacetate:toluene 1:1 as eluent.

A colourless oily substance was obtained (63% yield). The title compound17-(4-fluoro)-phenyl-18,19,20-trinor-PGF₂α -isopropyl ester 122 wasobtained as an oily substance, and purified by column chromato-graphy onsilica gel-60 using ethyl acetate as eluent (46% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.9 (1H m), 4.1 (2H m),5.0 (1H m), 5.4 (2H m), 5.5 (2H t), 6.9 (2H t), 7.1 (2H t).

EXAMPLE 23 Preparation of 20-(methylenephenyl)-PGF₂α -isopropyl ester123

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-7-phenyl heptyl phosphonate and was purified bycolumn chromatography on silica gel-60 using ethyl acetate:toluene 1:1as eluent. A colourless oily substance was obtained (68% yield).

The title compound 21-phenyl-21-homo-18,19,20-trinor-PGF₂α -isopropylester 123 was obtained as an oily substance, and purified by columnchromatography on silica gel-60 using ethyl acetate:hexane 1:0.5 aseluent (26% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 1.3 (6H m), 2.6 (2H t), 3.9 (1H m),4.1 (1H m), 4.2 (1H m), 5.0 (1H m), 5.4 (2H m), 5.5 (2H t), 7.2 (5H m).

EXAMPLE 24 Preparation of 17-naphthyl-18,19,20-trinor-PGF₂α -isopropylester 124

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-naphthyl-butyl-phosphonate giving a colourless oiltrans-enone lactone (30% yield).

The final product 17-naphthyl-18,19,20-trinor-PGF₂α -isopropyl ester 124was a colourless oil, and was purified by column chromatography onsilica gel-60 using ethyl acetateas eluent (15% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 3.2 (2H m), 3.9 (1H m), 4.2 (2H m),5.0 (1H m), 5.4 (2H m), 5.6 (2H t), 7.4 (4H m), 7.8 (4H m), 8.1 (1H d).

EXAMPLE 25 Preparation of 17-cyclohexyl-18,19,20-trinor-PGF₂α -isopropylester 125

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-cyclohexyl-butyl-phosphonate giving a colourlessoil trans-enone lactone (56% yield).

The final product 17-cyclohexyl-18,19,20-trinor-PGF₂α -isopropyl ester125 was a colourless oil, and was purified by column chromatography onsilica gel-60 using dichloromethane:isopro-panol 1:0,1 as eluent (30%yield). The chromatography was repeated suing ethyl acetate:hexane1:0,05 as eluent which affords a colourless oil. The product was driedunder vacuum.

¹ H-NMR (CDCl₃ /TMS): δ=0.9 (2H m), 1.2 (4H m), 1.2 (6H d), 3.9 (1H m),4.1 (1H 9), 4.2 (1H m), 5.0 (1H sept), 5.4 (2H m), 5.5 (2H m).

EXAMPLE 26 Preparation of 17-(4-metoxyphenyl)-18,19,20-trinor-PGF₂α-isopropyl ester 126

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(4-metoxy)-phenyl butyl phosphonate and waspurified by column chromatography on silica gel-60 using ethylacetate:toluene 1:1 as eluent. A colourless oily substance was obtained(65% yield).

The title compound 17-(4-metoxy)-phenyl-18,19,20-trinor-PGF₂α -isopropylester 126 was obtained as an oily substance, and purified by columnchromato-graphy on silica gel-60 using ethyl acetate:hexane 1:1 aseluent (30% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.8 (3H s), 3.9 (1H m),4.1 (1H m), 4.2 (1H m), 5.0 (1H m), 5.4 (2H m), 5.5 (2H m), 6.8 (2H d),7.1 (2H d).

EXAMPLE 27 Preparation of 17-(3-metoxyphenyl)-18,19,20-trinor-PGF₂α-isopropyl ester 127

Following a procedure similar to that described in example 7a (scheme 1)with modified step 7a-2, the aldehyde 29 described in 7a-1 was reactedwith dimethyl-2-oxo-4-(3-metoxy)-phenyl butyl phosphonate and waspurified by column chromatography on silica gel-60 using ethylacetate:toluene 1:1 as eluent. A colourless oily substance was obtained(57% yield).

The title compound 17-(3-metoxy)-phenyl-18,19,20-trinor-PGF₂α -isopropylester 127 was obtained as an oily substance, and purified by columnchromato-graphy on silica gel-60 using ethyl acetate:hexane 1:1 aseluent (20% yield).

¹ H-NMR (CDCl₃ /TMS): δ=1.2 (6H d), 2.6 (2H t), 3.8 (3H s), 3.9 (1H m),4.1 (2H m), 5.0 (1H m), 5.4 (2H m), 5.5 (2H m), 6.7 (3H t), 7.2 (1H t).

Studies of eye pressure lowering effect and adverse reactions

The intraocular pressure (IOP) was determined in animals with apneumatonometer (Digilab Modular One™, Bio Rad), specially calibratedfor the eye of the particular species. The cornea was anaesthetized with1-2 drops of oxibuprocain before each IOP measurement. In healthy humanvolunteers IOP was measured with applanation tonometry or with an airpuff tonometer (Keeler pulsair). For applanation tonometry either apneumatonometer (Digilab) or Goldmann's applanation tonometer mounted ona slit lamp microscope was used. The cornea was anaesthetized withoxibuprocain before each measurement with applanation tonometry. Nolocal anaesthesia was employed before measurement with the pulsairtonometer.

The ocular discomfort after application of the test substances wasevaluated in cats. The behavior of cats after topical application of thetest drug was followed and ocular discomfort was graded on a scale from0 to 3, 0 indicating complete absence of any signs of discomfort, and 3indicating maximal irritation as obvious from complete lid closure.

Conjunctival hyperemia after topical application of the test substanceswas evaluated in rabbits. The conjunctiva at the insertion of thesuperior rectus muscle of the eye was inspected or photographed withregular intervals and the degree of hyperemia was later evaluated fromthe color photographs in a blind manner. Conjunctival hyperemia wasevaluated on a scale from 0 to 4, 0 indicating complete absence of anyhyperemia, and 4 indicating marked hyperemia with conjunctival chemosis.

For determination of the effects on the intraocular pressure, primarilymonkeys (cynomolgus) were employed. The reason for this is that themonkey eye is highly reminiscent of the human eye and therefor,generally, drug effects are readily extrapolated to the human eye.However, the disadvantage of using the monkey eye as a model is that theconjunctiva in this species is pigmented making it impossible toevaluate conjunctival hyperemia and furthermore, the monkey eye isrelatively insensitive to irritation. Therefore, the cat eye, being verysensitive to prostaglandins was used for evaluating ocular discomfortand the rabbit eye with pronounced tendency to hyperemic reactions wasused for evaluating conjunctival and episcleral hyperemia.

It is evident from Table III that modification of the omega chain of theprostaglandin skeleton introduced new and unexpected features to theprostaglandins with respect to ocular irritation (discomfort).Particularly 17-phenyl,18,19,20-trinor-PGF₂α -IE and analogs were uniquein exhibiting a complete loss of ocular irritation with retained IOPlowering effect in monkeys. Whereas the 17-phenyl,18,19,20-trinor-PGF₂αderivatives were extremely well tolerated,16-phenyl-17,18,19,20-tetranor-PGF₂α -IE caused clear ocular discomfortalthough to a lesser degree than PGF₂α -IE or 15-propionate-PGE₂ -IE(Table III). However, substituting a hydrogen atom in the phenyl ringwith a methoxy group having electron donating properties rendered themolecule practically free of ocular irritating effect, Table III. It isalso evident from Table III that 18-phenyl-19,20,-dinor-PGF₂α IE,19-phenyl-20-nor-PGF₂α -IE as well as 17-phenyl-18,19,20-trinor-PGE₂ -IEand 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA₂ -IE, had no or verylittle irritating effect in the eye of cats. This indicates that theinvention not only is valid for 16-, and 17-tetra- and trinor analogs ofPGF₂α but for a range of omega chain modified and ring substitutedanalogs of PGF₂α (as exemplified with16-phenyl-17,18,19,20-tetranor-PGF₂α -IE to 19-phenyl-20-nor-PGF₂α -IE),and more importantly even for different members of the prostaglandinfamily such as PGE₂ and PGA₂ modified in an analogous way (Table III).Thus, modifying the omega chain and substituting a carbon atom in thechain with a ring structure introduces completely new, unexpected andadvantageous qualities to naturally occuring prostaglandins in that theirritating effect in the conjunctiva and cornea is abolished. In thecase of 16-phenyl-17,18,19,20-tetranor-PGF₂α -IE exhibiting someirritating effect substituting a hydrogen atom in the ring structurewith e.g. a methoxy group attenuates or abolishes the irritating effect.

In addition to the lack of ocular discomfort the omega chain modifiedanalogs also exhibited an advantage over naturally occuringprostalgandins in that they caused considerably less conjunctivalhyperemia as studied in the rabbit eye (Table IV). Particularly,15-Dehydro-17-phenyl-18,19,20-trinor-PGF₂α-IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α -IE, and13,14-dihydro-17-phenyl-18,19,20-trinor PGA₂ -IE were advantageous inthis respect. Also 18-phenyl-19,20-dinor-PGF₂α -IE and19-phenyl-20-nor-PGF₂α -IE induced very little conjunctival hyperemia(Table IV).

The intraocular pressure lowering effect of omega chain modified andring-substituted prostaglandin analogs is demonstrated in Table V. Itcan be seen that particularly 16-phenyl-tetranor and 17-phenyl-trinorprostaglandin analogs significantly reduced IOP in animal eyes (TableV). In all but two series of experiments cynomolgus monkeys were used.It is of particular interest to note that 17-phenyl-18,19,20-trinorPGF₂α -derivatives exhibiting no ocular irritation and only modestconjunctival/episcleral hyperemia significantly lowered IOP in primates.It should furthermore be observed that both16-phenyl-17,18,19,20-tetranor-PGF.sub.α -IE,18-phenyl-19,20-dinor-PGF₂α -IE and 19-phenyl-20-nor-PGF.sub.α -IEreduced the intraocular pressure, thus, modification of the omega chainand substituting a carbon atom in the chain with a ring structure do notrender the molecule inactive with respect to the effect on theintraocular pressure.

Furthermore, it should be observed that substituting a hydrogen on thering structure of 16-phenyl, 17,18,19,20-tetranor-PGF₂α -IE with amethoxy group eliminated much of the ocular irritating effect preservingmost of the intraocular pressure lowering effect. Thus, omega chainmodified and ring substituted prostaglandin analogs reduce IOPeffectively in animals. It is further demonstrated in Table V that16-phenoxy-17,18,19,10-tetranor-PGF₂α -IE effectively lowers theintraocular pressure as studied in cats. Thus, substituting carbon 17 inthe omega chain with a hetero atom, in this case oxygen, does not renderthe molecule inactive with respect to the effect on IOP.

It is noteworthy that most of the 17-phenyl,18,19,20-trinorprostaglandin analogs had poor intraocular pressurelowering effect in cats, even at high doses. It is to be observed thatthe doses at which compounds were used presented in Table III are lowerthan those e.g. in Table V. Doses presented in Table III should beexplicitly compared with those of the naturally occuring prostaglandinsin the same table. The same is true for Table IV. It is clear that withincreasing dose side effects may increase. However, the doses ofprostaglandin derivatives used in monkeys are comparatively similar tothose used in human volunteers, (Table VI) being practically free ofside effects.

The effect of some omega chain modified prostaglandin analogs, morespecifically 17-phenyl-18,19,20-trinor-PGF₂α -IE,15-dehydro-17-phenyl-18,19,20-trinor-PGF₂α -IE,15-(R)-17-phenyl-18,19,20-trinor-PGF₂α -IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α -IE, and18-phenyl-19-20-dinor-PGF₂α -IE on the intraocular pressure of healthyhuman volunteers is demonstrated in Table VI. All compoundssignificantly reduced the intraocular pressure. It is particularlysignificant in this respect that none of the compounds had anysignificant irritating effect (ocular discomfort) and that13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂α -IE and15-dehydro-17-phenyl-18,19,20-trinor-PGF₂α -IE caused very little if anyconjunctival/episcleral hyperemia in man. Thus, omega chain modified,and ring substituted prostaglandin analogs seem to be unique in thatthese compounds reduce IOP without causing significant ocular sideeffects such as hyperemia and discomfort.

The present invention thus describes a group of compounds exhibiting theunique property of causing insignificant ocular side effects whileretaining the intraocular pressure lowering effect. From the foregoingit is evident that the crucial modification of the molecule is a ringstructure in the omega chain. Furthermore, substituents in the ringstructure and/or in the omega chain may be introduced in certainmolecules still exhibiting some side-effects in the eye. Hetero atomsmay also be introduced into the ring substituted omega chain. Presently,particularly 17-phenyl-18,19,20-trinor-PGF₂α -derivatives seem verypromising for therapeutic use in glaucoma. From the scientificliterature it is evident that PGE₂ and PGA₂ or their esters lower IOP inthe monkey (see Bito et al, 1989). Clinical studies with PGE₂ have alsobeen performed demonstrating IOP-lowering effect in man (Flach andEliason (1988)). Thus, the analogy with PGF₂α and its esters loweringIOP in the primate eye is logic. It is most reasonable to assume thatother prostaglandins with modified omega chain exhibit essentially thesame properties as PGF₂α with modified omega chain, i.e. IOP loweringeffect without side effects.

The results from an experiment in which the substance13,14-dihydro-15-dehydro-17-phenyl-18,19,20-trinor-PGF₂α-isopropylester, from Example 12, was administered in two healthyvolunteers whereby each person received one drop of a test formulationcontaining 5 μg of the active substance immediately after theintraocular pressure had been measure at time Oh. The contralateralcontrol eye received only the vehicle. The pressure was then measuredafter 4, 7 and 9 hours and the following results measured with a pulsairtonometer were obtained. All the results are given in mmHg.

    ______________________________________                                                     Time after administration                                        Person  Eye        0 h    4 h     7 h  9 h                                    ______________________________________                                        1       Exp        13.4   12.3    11.0 11.9                                           Contr      13.9   12.2    12.5 13.4                                   2       Exp        14.0   12.6    12.3 11.2                                           Contr      12.3   13.0    13.2 12.0                                   ______________________________________                                    

These results show that the substance indeed reduces the intraocularpressure although the starting pressures (at Oh) in these specificexamples were very low. Most strikingly, there were no side effectsobserved in any of the persons, neither conjunctival hyperemia norsuperficial ocular irritation in the form of grittiness or foreign bodyfeeling.

                  TABLE I                                                         ______________________________________                                         ##STR5##                     1                                                ##STR6##                     2                                                ##STR7##                     3                                                ##STR8##                     4                                                ##STR9##                     5                                                ##STR10##                    6                                                ##STR11##                    7                                                ##STR12##                    8                                                ##STR13##                    9                                                ##STR14##                    10                                               ##STR15##                    20                                               ##STR16##                    112                                              ##STR17##                    113                                              ##STR18##                    114                                              ##STR19##                    115                                              ##STR20##                    116                                              ##STR21##                    117                                              ##STR22##                    118                                              ##STR23##                    119                                              ##STR24##                    120                                              ##STR25##                    121                                              ##STR26##                    122                                              ##STR27##                    123                                              ##STR28##                    124                                              ##STR29##                    125                                              ##STR30##                    126                                              ##STR31##                    127                                              ##STR32##                    128                                             ______________________________________                                    

                  TABLE II                                                        ______________________________________                                         ##STR33##                                                                     ##STR34##                                                                     ##STR35##                                                                     ##STR36##                                                                     ##STR37##                                                                     ##STR38##                                                                     ##STR39##                                                                     ##STR40##                                                                     ##STR41##                                                                    ______________________________________                                    

    ______________________________________                                                           Dose     Degree of                                         Substance          (μg)  occular irritation                                ______________________________________                                        PGF.sub.2α -isopropylester (-IE)                                                           1        3.0 ± 0.0                                      15-propionate-PGE.sub.2 -IE                                                                      0.1-1    3.0 ± 0.0                                      15-propionate-PGD.sub.2 -IE                                                                      1        1.3 ± 0.2                                      17-phenyl-18,19,20-                                                                              1-5      0                                                 trinor-PGF.sub.2α -IE (2)                                               15-dehydro-17-phenyl-                                                                            5        0                                                 18,19,20-trinor-                                                              PGF.sub.2α -IE (3)                                                      15-(R)-17-phenyl-  1-5      0                                                 18,19,20-trinor-PGF.sub.2α IE (7)                                       13,14-dihydro-17-phenyl-                                                                         1        0                                                 18,19,20-trinor-PGF.sub.2α -IE (9)                                      17-phenyl-18,19,20-                                                                                0.3    0                                                 trinor-PGE.sub.2 -IE (5)                                                      13,14-dihydro-17-phenyl-                                                                         1        0                                                 18,19,20-trinor-PGA.sub.2 -IE (6)                                             16-phenyl-17,18,19,20-                                                                           1        2.2 ± 0.3                                      tetranor-PGF.sub.2α -IE (1)                                             16-[4-(methoxy)-phenyl]-                                                                         1        0.2 ± 0.1                                      17,18,19,20-tetranor-                                                         PGF.sub.2α -IE (8)                                                      18-phenyl-19,20-dinor-                                                                           1        0.7 ± 0.1                                      PGF.sub.2α -IE (10)                                                     19-phenyl-20-nor-PGF.sub.20α -IE (20)                                                      1        0.5 ± 0.1                                      16-phenoxy-17,18,19,20-                                                                          5        0.3 ± 0.2                                      tetranor-PGF.sub.2α -IE (4)                                             ______________________________________                                    

    ______________________________________                                                             Dose   Degree of                                         Substance            (μg)                                                                              hyperemia                                         ______________________________________                                        PGF.sub.2α -isopropylester (-IE)                                                             0.1    2.8 ± 0.2                                      15-propionate-PGE.sub.2 -IE                                                                        0.5    2.7 ± 0.3                                      16-phenyl-17,18,19,20-                                                                             0.5    1.3 ± 0.9                                      tetranor-PGF.sub.2α -IE (1)                                             17-phenyl-18,19,20-trinor-                                                                         0.5    2.0 ± 0.3                                      PGF.sub.2α -IE (2)                                                      15-dehydro-17-phenyl-                                                                              0.5    0.7 ± 0.3                                      18,19,20-trinor-PGF.sub.2α -IE (3)                                      15-(R)-17-phenyl-18,19,20-                                                                         0.5    2.0 ± 0.0                                      trinor-PGF.sub.2α -IE (7)                                               13,14-dihydro-17-phenyl-                                                                           0.5    1.3 ± 0.3                                      18,19,20-trinor-PGF.sub.2α -IE (9)                                      17-phenyl-18,19,20-trinor-                                                                         0.5    2.7 ± 0.2                                      PGE.sub.2 -IE (5)                                                             13,14-dihydro-17-phenyl-                                                                           0.5    0.3 ± 0.3                                      18,19,20-trinor-PGA.sub.2 -IE (6)                                             18-phenyl-19,20-dinor-                                                                             0.5    0.3 ± 0.2                                      PGF.sub.2α -IE (10)                                                     19-phenyl-20-nor-PGF.sub.2α -IE (20)                                                         0.5    0.2 ± 0.2                                      16-phenoxy-17,18,19,20-                                                                            0.5    2.3 ± 0.3                                      tetranor-PGF.sub.2α -IE (4)                                             ______________________________________                                    

                                      TABLE V                                     __________________________________________________________________________    Intraocular pressure reducing effect of naturally occuring prostaglandin      (PGF.sub.2α) and                                                        omega chain modified analogs as determined in cynomolgus monkeys or cats.     Unless                                                                        specified data were obtained in monkeys. The figures within parenthesis       refer to                                                                      formulas given in Table I.                                                                        Time after administration (hours)                                             0       1-2   3-4   6                                     Substance     Dose (μg)                                                                        (mm Hg) (mm Hg)                                                                             (mm Hg)                                                                             (mm Hg)                               __________________________________________________________________________    PGF.sub.2α -isopropylester (IE)                                                       1.5   E 11.4 ± 0.7                                                                        8.3 ± 0.5*                                                                       8.0 ± 0.6                                                                        9.3 ± 0.8                                             C 11.0 ± 0.7                                                                       10.7 ± 0.4                                                                       10.1 ± 0.4                                                                       10.6 ± 0.9                         16-phenyl-17,18,19,20-                                                                      3.2   E 12.7 ± 1.1                                                                       11.8 ± 1.1                                                                        9.1 ± 0.8*                                                                       8.4 ± 0.7*                        IE (1)or-PGF.sub.2α                                                                         C 12.8 ± 0.5                                                                       14.0 ± 0.2                                                                       13.0 ± 0.8                                                                       11.7 ± 0.8                         17-phenyl-18,19,20-                                                                         3.2   E 12.8 ± 0.5                                                                        8.6 ± 0.3*                                                                       9.5 ± 0.7                               trinor-PFG.sub.2α -IE (2)                                                                   C 13.4 ± 0.6                                                                       11.7 ± 0.6                                                                       12.4 ± 0.2                                                                       11.9 ± 0.7                         13,14-dihydro-17-phenyl-                                                                    10.4  E 11.1 ± 0.9                                                                        8.3 ± 0.6                                                                        6.9 ± 0.4*                                                                       7.7 ± 0.8                         18,19,20-trinor-PGF.sub.2α -IE (9)                                                          C 10.6 ± 0.7                                                                        8.8 ± 0.9                                                                       10.3 ± 1.1                                                                        9.5 ± 1.0                         18-phenyl-19,20-dinor-                                                                      3.1   E  9.7 ± 0.9                                                                        9.6 ± 1.1                                                                        9.6 ± 0.7                                                                        8.8 ± 0.9*                        PFG.sub.2α -IE (10)                                                                         C 10.1 ± 1.0                                                                        9.4 ± 1.2                                                                        9.8 ± 1.2                                                                        9.4 ± 0.9                         16-phenyl-17,18,19,20-                                                                      5**   E 2.05 ± 1.2                                                                       25.7 ± 1.2                                                                       19.2 ± 1.8                                                                       15.0 ± 1.2*                        tetranor-PGF.sub.2α -IE (4)                                                                 C 20.7 ± 1.2                                                                       22.7 ± 1.1                                                                       19.5 ± 0.9                                                                       19.2 ± 0.8                         16-[4-(methoxy)-phenyl]-                                                                    3.2   E 11.2 ± 0.9                                                                       10.5 ± 1.3                                                                        9.8 ± 1.4*                                                                       9.2 ± 0.9                         17,18,19,20-tetranor-                                                                             C 10.4 ± 1.1                                                                       10.9 ± 1.0                                                                       11.3 ± 1.4                                                                        9.2 ± 0.6                         PGF.sub. 2α -IE (8)                                                     19-phenyl-20-nor-                                                                           1**   E 16.9 ± 1.0                                                                       16.6 ± 0.7                                                                       15.8 ± 0.8*                                                                      18.1 ± 1.2                         PFG.sub.2α -IE (20)                                                                         C 17.1 ± 0.4                                                                       18.1 ± 0.6                                                                       18.9 ± 0.6                                                                       19.2 ± 0.8                         __________________________________________________________________________     *Indicates statistical significance p < 0.05. The substances were applied     topically.                                                                    **Data obtained in cat eyes.                                             

                                      TABLE VI                                    __________________________________________________________________________    Intraocular pressure reducing effect of different omega chain modified        and ring                                                                      substituted PGF.sub.2α -IE analogs in healthy human volunteers. The     substance number is given within                                              paranthesis.                                                                                          Time after administration (hours)                                    Dose     0     4     6     8                                   Substance      (μg)                                                                          n Eye (mm Hg)                                                                             (mm Hg)                                                                             (mm Hg)                                                                             (mm Hg)                             __________________________________________________________________________    17-phenyl-18,19,20-trinor-                                                                   1  4 Exp 11.9 ± 1.7                                                                       11.0 ± 0.9*                                                                      10.1 ± 0.7*                                                                       9.8 ± 0.7*                      PGF.sub.2α -isopropylester (IE) (2)                                                         Contr                                                                             12.7 ± 1.7                                                                       13.9 ± 0.7                                                                       13.5 ± 1.2                                                                       12.5 ± 0.7                       15-(R)-17-phenyl-18,19,20-                                                                   10 3 Exp 12.9 ± 0.9                                                                       11.8 ± 0.6                                                                       11.0 ± 0.3                                                                       11.2 ± 1.3*                      IE (7)-PGF.sub.2α                                                                           Contr                                                                             13.2 ± 1.4                                                                       13.7 ± 0.9                                                                       13.8 ± 1.0                                                                       15.1 ± 1.3                       15-dehydro-17-phenyl-                                                                        10 4 Exp 17.7 ± 0.6                                                                       14.6 ± 0.2                                                                       13.6 ± 0.7                                                                       --                                  18,19,20-trinor-PFG.sub.2α -IE (3)                                                          Contr                                                                             17.5 ± 0.7                                                                       16.4 ± 0.5                                                                       16.3 ± 1.0                                                                       --                                  13,14-dihydro-17-phenyl-                                                                     1  4 Exp 14.2 ± 0.5                                                                       13.3 ± 1.1                                                                       12.2 ± 0.4                                                                       12.5 ± 0.9                       18,19,20-trinor-PGF.sub.2α -IE (9)                                                          Contr                                                                             13.5 ± 0.6                                                                       14.2 ± 1.2                                                                       15.2 ± 1.0                                                                       15.1 ± 0.7                       18-phenyl-19,20-dinor-                                                                       5  3 Exp 14.4 ± 1.0                                                                       12.2 ± 1.1                                                                       12.4 ± 1.2                                                                       11.9 ± 0.7*                      PFG.sub.2α -IE (10)                                                                         Contr                                                                             15.2 ± 0.1                                                                       13.7 ± 1.2                                                                       14.4 ± 0.2                                                                       13.2 ± 0.5                       __________________________________________________________________________     *Indicates statistical significance p < 0.05.                            

                  TABLE VII                                                       ______________________________________                                        Irritative effect of omega chain modified                                     prostaglandin analogues in the cat eye. All analogues have                    been tested as isopropyl esters.                                              Scale of discomfort from 0 to 3.                                              Substance           Subst. no                                                                              Dose   Irritation                                ______________________________________                                        24-phenyl-21,22,23,24-tetrahomo-                                                                  113      3.0    0.0 ± 0.0                              PGF.sub.2α -isopropylester                                              17-(2-thiophene)-18,19,20-trinor-                                                                 114      1.0    0.0 ± 0.0                              PGF.sub.2α -isopropylester                                              17-cyclohexyl-18,19,20-trinor                                                                     125      1.0    0.3 ± 0.0                              PGF.sub.2α -isopropylester                                              17-(4-methyl)-phenyl-18,19,20-trinor                                                              120      5.0    0.0 ± 0.0                              PGF.sub.2α -isopropylester                                              17-(2-methyl)-phenyl-18,19,20-trinor                                                              121      5.0    0.0 ± 0.0                              PGF.sub.2α -isopropylester                                              17-(4-trifluoromethyl)-phenyl-                                                                    118      10.0   0.0 ± 0.0                              18,19,20-trinor-PGF.sub.2α -isopropylester                              17-(4-fluoro)-phenyl-18,19,20-                                                                    122      5.0    0.0 ± 0.0                              trinor-PGF.sub.2α -isopropylester                                       17-S-methyl-17-phenyl-18,19,20-                                                                   117      5.0    0.0 ± 0.0                              trinor-PGF.sub.2α -isopropylester                                       13,14-dihydro-15-dehydro-17-phenyl-                                                               119      5.0    0.0 ± 0.0                              18,19,20-trinor-PGF.sub.2α -isopropylester                              ______________________________________                                    

                  TABLE VIII                                                      ______________________________________                                        Effect of omega chain modified prostaglandin analogues on                     conjunctival hyperemia (dilatation of blood vessels in the                    conjunctiva of the eye) in the rabbit. All analogues have been                studied as isopropyl esters and have been applied topically on                the eye. Hyperemia was scored using a scale from 0 to 4.                                          Subst.                                                    Substance           no      Dose   Hyperemia                                  ______________________________________                                        PGF.sub.2α -isopropylester                                                                  --      0.5    2.8 ± 0.2                               24-phenyl-21,22,23,24-tetrahomo-                                                                  113     0.5    0.2 ± 0.2                               PGF.sub.2α -isopropylester                                              17-(2-thiophene)-18,19,20-trinor-                                                                 114     0.5    1.2 ± 0.4                               PGF.sub.2α -isopropylester                                              17-cyclohexyl-18,19,20-trinor                                                                     125     0.5    1.4 ± 0.5                               PGF.sub.2α -isopropylester                                              17-(4-methyl)-phenyl-18,19,20-trinor                                                              120     0.5    0.5 ± 0.3                               PGF.sub.2α -isopropylester                                              17-(2-methyl)-phenyl-18,19,20-trinor                                                              121     0.5    1.3 ± 0.3                               PGF.sub.2α -isopropylester                                              17-(4-trifluoromethyl)-phenyl-                                                                    118     0.5    1.2 ± 0.2                               18,19,20-trinor-PGF.sub.2α -isopropylester                              17-(4-fluoro)-phenyl-18,19,20-                                                                    122     0.5    2.3 ± 0.3                               trinor-PGF.sub.2α -isopropylester                                       17-S-methyl-17-phenyl-18,19,20-                                                                   117     0.5    1.2 ± 0.4                               trinor-PGF.sub.2α -isopropylester                                       13,14-dihydro-15-dehydro-17-phenyl-                                                               119     0.5    0.2 ± 0.2                               18,19,20-trinor-PGF.sub.2α -isopropylester                              ______________________________________                                    

                                      TABLE IX                                    __________________________________________________________________________    Effect of omega chain modified protaglandin analogues on the intraocular      pressure in                                                                   normotensive unanaesthetized cynomolgus monkeys. All analogues have been      tested as the isopropyl                                                       esters in aqueous solution and they have been applied in one eye while        the other eye has                                                             received the vehicle only. The experimental eye has been compared with        the contralateral control                                                     (vehicle) eye.                                                                                          Time after administration                           Substance         Dose μg                                                                         Eye                                                                              0 h   1 h   2 h   4 h   6 h                         __________________________________________________________________________    17-(2-thiophene)-18,19,20-trinor-                                                               3.0  E  13.3 ± 2.0                                                                       10.8 ± 0.8                                                                        9.3 ± 1.7                                                                       10.0 ± 1.1                                                                       11.6 ± 2.3               PGF.sub.2α -isopropylester (114)                                                               C  12.8 ± 1.9                                                                       11.8 ± 1.6                                                                        9.2 ± 1.7                                                                       10.0 ± 1.5                                                                       10.5 ± 1.7               17-cyclohexyl-18,19,20-trinor                                                                   10.0 E  11.2 ± 1.2                                                                       11.3 ± 0.7                                                                       11.0 ± 1.0                                                                       10.5 ± 1.6                                                                        9.7 ± 1.0*              PGF.sub.2α -isopropylester (125)                                                               C  11.3 ± 1.2                                                                       10.9 ± 0.8                                                                       10.0 ± 0.9                                                                       11.1 ± 1.2                                                                       11.2 ±  1.0              17-(4-methyl)-phenyl-18,19,20-trinor                                                            10.0 E  10.7 ± 1.3                                                                        9.4 ± 0.8                                                                        9.6 ± 0.4                                                                        8.6 ± 0.5*                                                                       8.5 ± 0.2*              PGF.sub.2α -isopropylester (120)                                                               C  10.4 ± 1.0                                                                        9.4 ± 0.8                                                                        9.2 ± 0.4                                                                       10.2 ± 0.5                                                                       10.7 ± 0.5               17-(2-methyl)-phenyl-18,19,20-trinor                                                            10.0 E  11.9 ± 0.5                                                                       11.3 ± 1.4                                                                       12.5 ± 1.5                                                                        9.9 ± 1.1*                                                                      10.4 ± 0.7               PGF.sub.2α -isopropylester (121)                                                               C  11.7 ± 0.5                                                                       11.9 ± 1.3                                                                       12.5 ± 1.5                                                                       12.1 ± 1.1                                                                       10.4 ± 1.1               17-(4-trifluoromethyl)-phenyl-18,19,                                                            10.0 E  10.8 ± 1.5                                                                       10.7 ± 0.9                                                                       10.3 ± 1.3*                                                                       9.0 ± 1.1*                                                                      10.1 ± 1.4*              20-trinor-PGF.sub.2α -isopropylester (118)                                                     C  10.8 ± 1.4                                                                       11.5 ± 1.3                                                                       11.4 ± 1.6                                                                        9.8 ± 1.1                                                                       11.0 ± 1.5               17-(4-fluoro)-phenyl-18,19,20-                                                                  1.0  E   9.7 ± 1.0                                                                        8.9 ± 0.6                                                                        8.6 ± 1.0                                                                        6.5 ± 0.7*                                                                       6.8 ± 0.5*              trinor-PGF.sub.2α -isopropylester (122)                                                        C   9.7 ±  1.0                                                                       8.9 ± 0.6                                                                        8.8 ± 1.0                                                                        8.4 ± 0.9                                                                        9.8 ± 1.2               17-S-methyl-17-phenyl-18,19,20-                                                                 10.0 E  11.9 ± 0.3                                                                       10.9 ± 1.2                                                                        8.8 ± 0.7                                                                        8.4 ± 0.6                                                                        8.3 ± 0.6               trinor-PGF.sub.2α -isopropylester (117)                                                        C  12.0 ± 0.4                                                                       10.9 ± 1.2                                                                        8.8 ± 0.7                                                                        9.3 ± 0.9                                                                        8.6 ± 0.6               13,14-dihydro-15-dehydro-17-phenyl-                                                             3.0  E  10.6 ± 1.3                                                                        9.0 ± 0.6                                                                        8.2 ± 1.0                                                                        8.9 ± 1.0                                                                        9.3 ± 1.1               18,19,20-trinor-PGF.sub.2α -isopropylester                                                     C  10.6 ± 1.2                                                                        8.7 ± 0.7                                                                        8.6 ± 0.7                                                                        9.6 ± 0.7                                                                       10.0 ± 1.1               (119)                                                                         __________________________________________________________________________     *p 32  0.05 (ttest)                                                           ##STR42##

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We claim:
 1. A therapeutic composition for topical treatment of ocularhypertension or glaucoma comprising therapeutically effective amount ofa PGF₂α isopropyl ester, containing a ring structure, substituted orunsubstituted, on the omega chain, selected from the group consistingof20-phenyl-PGF₂α isopropyl ester, 20-(4-phenylbutyl)-PGF₂α isopropylester, 17-(2-thiophene-18,19,20-trinor-PGF₂α -isopropyl ester,17-(3-thiophene-18,19,20-trinor-PGF₂α -isopropyl ester,17-methyl-17-phenyl-18,19,20-trinor-PGF₂α -isopropyl ester,17-(4-trifluoromethyl phenyl)-18,19,20-trinor-PGF₂α -isopropyl ester,17-(4-methylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester,17-(2-methylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester,17-(4-fluorophenyl)-18,19,20-trinor-PGF₂α -isopropyl ester,20(methylenephenyl)-PGF₂α -isopropyl ester,17-napthyl-18,19,20-trinor-PGF₂α -isopropyl ester,17-cyclohexyl-18,19,20-trinor-PGF₂α -isopropyl ester,17-(4-methoxyphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester,17-(3-methoxyphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester,15-cyclohexyl-16,17,18,19,20-pentanor-PGF₂α isopropyl ester.
 2. Atherapeutic composition of claim 1, comprising 20-phenyl-PGF₂α isopropylester.
 3. A therapeutic composition of claim 1, comprising20-(4-phenylbutyl)-PGF₂α isopropyl ester.
 4. A therapeutic compositionof claim 1, comprising 17-(2-thiophene-18,19,20-trinor-PGF₂α -isopropylester.
 5. A therapeutic composition of claim 1, comprising17-(3-thiophene-18,19,20-trinor-PGF₂α -isopropyl ester.
 6. A therapeuticcomposition of claim 1, comprising17-methyl-17-phenyl-18,19,20-trinor-PGF₂α -isopropyl ester.
 7. Atherapeutic composition of claim 1, comprising 17-(4-trifluoromethylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester.
 8. A therapeuticcomposition of claim 1, comprising17-(4-methylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester.
 9. Atherapeutic composition of claim 1, comprising17-(2-methylphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester.
 10. Atherapeutic composition of claim 1, comprising17-(4-fluorophenyl)-18,19,20-trinor-PGF₂α -isopropyl ester.
 11. Atherapeutic composition of claim 1, comprising 20(methylenephenyl)-PGF₂α-isopropyl ester.
 12. A therapeutic composition of claim 1, comprising17-napthyl-18,19,20-trinor-PGF₂α -isopropyl ester.
 13. A therapeuticcomposition of claim 1, comprising 17-cyclohexyl-18,19,20-trinor-PGF₂α-isopropyl ester.
 14. A therapeutic composition of claim 1, comprising17-(4-methoxyphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester.
 15. Atherapeutic composition of claim 1, comprising17-(3-methoxyphenyl)-18,19,20-trinor-PGF₂α -isopropyl ester.
 16. Atherapeutic composition of claim 1, comprising15-cyclohexy-16,17,18,19,20-pentanor-PGF₂α isopropyl ester.
 17. A methodof treating ocular hypertension or glaucoma by topical application ofthe therapeutic composition of claim 1.